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    Clinical Trial Results:
    A Randomized, International, Double-Blinded (With In-House Blinding), Controlled With GARDASIL™, Dose-Ranging, Tolerability, Immunogenicity, and Efficacy Study of a Multivalent Human Papillomavirus (HPV) L1 Virus-Like Particle (VLP) Vaccine Administered to 16- to 26-Year-Old Women

    Summary
    EudraCT number
    2007-003528-39
    Trial protocol
    DK   SE   DE   AT   Outside EU/EEA  
    Global end of trial date
    07 Jul 2016

    Results information
    Results version number
    v1(current)
    This version publication date
    04 Jan 2017
    First version publication date
    04 Jan 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    V503-001
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT00543543
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Merck Sharp & Dohme Corp.
    Sponsor organisation address
    2000 Galloping Hill Road, Kenilworth, NJ, United States, 07033
    Public contact
    Clinical Trials Disclosure, Merck Sharp & Dohme Corp., ClinicalTrialsDisclosure@merck.com
    Scientific contact
    Clinical Trials Disclosure, Merck Sharp & Dohme Corp., ClinicalTrialsDisclosure@merck.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    EMEA-000654-PIP01-09
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    07 Jul 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    07 Jul 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The purpose of this study was to evaluate the safety, efficacy, and immunogenicity of V503 in comparison to GARDASIL. The primary hypotheses tested in the study were 1) V503 administered to 16- to 26-year-old adolescents and young women is generally well-tolerated, 2) V503 reduces combined incidence of Human Papillomavirus (HPV) Type 31/33/45/52/58-related disease compared with GARDASIL, and 3) V503 induces non-inferior geometric mean titers for HPV Type 6/11/16/18 antibodies compared with GARDASIL. The study included a dose-finding evaluation of a 3-dose regimen of V503 and GARDASIL, a safety/efficacy evaluation of a 3-dose regimen of the selected V503 dose formulation and GARDASIL, and an extension consisting of 2 substudies: an evaluation of immune memory in participants receiving a fourth vaccination with V503 (Cohort 1), and an opportunity for participants who received GARDASIL in the Base Study to receive a 3-dose regimen of V503 (Cohort 2).
    Protection of trial subjects
    This study was conducted in conformance with Good Clinical Practice standards and applicable country and/or local statutes and regulations regarding ethical committee review, informed consent, and the protection of human subjects participating in biomedical research. The following additional measure(s) defined for this individual study was (were) in place for the protection of trial subjects: participants who received GARDASIL in the Base Study will have the opportunity to receive a 3-dose regimen of V503 in the study extension (Cohort 2).
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    24 Sep 2007
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Sweden: 128
    Country: Number of subjects enrolled
    Taiwan: 600
    Country: Number of subjects enrolled
    Thailand: 465
    Country: Number of subjects enrolled
    United States: 1572
    Country: Number of subjects enrolled
    Austria: 168
    Country: Number of subjects enrolled
    Brazil: 765
    Country: Number of subjects enrolled
    Canada: 1442
    Country: Number of subjects enrolled
    Chile: 140
    Country: Number of subjects enrolled
    Colombia: 2499
    Country: Number of subjects enrolled
    Denmark: 3731
    Country: Number of subjects enrolled
    Germany: 194
    Country: Number of subjects enrolled
    Hong Kong: 160
    Country: Number of subjects enrolled
    Japan: 254
    Country: Number of subjects enrolled
    Korea, Republic of: 307
    Country: Number of subjects enrolled
    Mexico: 781
    Country: Number of subjects enrolled
    New Zealand: 97
    Country: Number of subjects enrolled
    Norway: 710
    Country: Number of subjects enrolled
    Peru: 785
    Country: Number of subjects enrolled
    Puerto Rico: 42
    Worldwide total number of subjects
    14840
    EEA total number of subjects
    4931
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    343
    Adults (18-64 years)
    14497
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    The study enrolled healthy young women 16 to 26 years of age.

    Pre-assignment
    Screening details
    A total of 15,334 participants were screened and 14,840 were randomized into the study.

    Period 1
    Period 1 title
    Base Study
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Low-dose V503
    Arm description
    V503 (9-Valent Human Papillomavirus [HPV] Vaccine) low-dose 0.5 mL injection in a 3-dose regimen in the Base Study.
    Arm type
    Experimental

    Investigational medicinal product name
    V503 9-valent HPV (Types 6, 11, 16, 18, 31, 33, 45, 52, and 58) L1 virus-like particle vaccine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    0.5 mL injection in the non-dominant deltoid muscle on Day 1, Month 2 and Month 6 of the Base Study

    Arm title
    Mid-dose V503
    Arm description
    V503 mid-dose 0.5 mL injection in a 3-dose regimen in the Base Study. A subset of participants will receive a fourth V503 mid-dose vaccination in the extension study (Cohort 1).
    Arm type
    Experimental

    Investigational medicinal product name
    V503 9-valent HPV (Types 6, 11, 16, 18, 31, 33, 45, 52, and 58) L1 virus-like particle vaccine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    0.5 mL injection in the non-dominant deltoid muscle on Day 1, Month 2 and Month 6 of the Base Study

    Arm title
    High-dose V503
    Arm description
    V503 high-dose 0.5 mL injection in a 3-dose regimen in the Base Study
    Arm type
    Experimental

    Investigational medicinal product name
    V503 9-valent HPV (Types 6, 11, 16, 18, 31, 33, 45, 52, and 58) L1 virus-like particle vaccine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    0.5 mL injection in the non-dominant deltoid muscle on Day 1, Month 2 and Month 6 of the Base Study

    Arm title
    Gardasil
    Arm description
    Gardasil (4-Valent HPV Vaccine) 0.5 mL injection in a 3-dose regimen in the Base Study. Participants will be offered the V503 mid-dose 3-dose regimen in the extension study (Cohort 2).
    Arm type
    Active comparator

    Investigational medicinal product name
    GARDASIL (4-Valent HPV [Types 6, 11, 16, and 18] L1 virus-like particle vaccine)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    0.5 mL injection in the non-dominant deltoid muscle on Day 1, Month 2 and Month 6 of the Base Study

    Number of subjects in period 1
    Low-dose V503 Mid-dose V503 High-dose V503 Gardasil
    Started
    315
    7106
    310
    7109
    Completed 3 vaccinations in Base Study
    300
    6928
    297
    6934
    Completed
    295
    5854
    296
    5887
    Not completed
    20
    1252
    14
    1222
         Protocol deviation
    -
    6
    -
    6
         Physician decision
    -
    4
    -
    7
         Adverse event, non-fatal
    1
    11
    -
    5
         Consent withdrawn by subject
    7
    482
    5
    503
         Lost to follow-up
    12
    749
    9
    701
    Period 2
    Period 2 title
    Extension Study
    Is this the baseline period?
    No
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Mid-dose V503 (Cohort 1)
    Arm description
    V503 (9-Valent HPV Vaccine) mid-dose 0.5 mL fourth dose administration on Base Study participants who were randomized to receive a 3-dose regimen of V503 (9-Valent HPV) mid-dose 0.5 mL (Cohort 1).
    Arm type
    Experimental

    Investigational medicinal product name
    V503 9-valent HPV (Types 6, 11, 16, 18, 31, 33, 45, 52, and 58) L1 virus-like particle vaccine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    0.5 mL injection in the non-dominant deltoid muscle on Day 1, Month 2 and Month 6 of the Base Study

    Investigational medicinal product name
    V503 9-valent HPV (Types 6, 11, 16, 18, 31, 33, 45, 52, and 58) L1 virus-like particle vaccine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    0.5 mL injection in the non-dominant deltoid muscle at Month 60 in the Extension Study

    Arm title
    Mid-dose V503 (Cohort 2)
    Arm description
    V503 (9-Valent HPV Vaccine) mid-dose 0.5 mL 3-dose regimen administration on Base Study participants who were randomized to receive a 3-dose regimen of Gardasil (4-Valent HPV Vaccine) (Cohort 2).
    Arm type
    Experimental

    Investigational medicinal product name
    V503 9-valent HPV (Types 6, 11, 16, 18, 31, 33, 45, 52, and 58) L1 virus-like particle vaccine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    0.5 mL injection in the non-dominant deltoid muscle at Month 60, 62 and 66 of the Extension Study

    Investigational medicinal product name
    GARDASIL (4-Valent HPV [Types 6, 11, 16, and 18] L1 virus-like particle vaccine)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    0.5 mL injection in the non-dominant deltoid muscle on Day 1, Month 2 and Month 6 of the Base Study

    Number of subjects in period 2 [1]
    Mid-dose V503 (Cohort 1) Mid-dose V503 (Cohort 2)
    Started
    150
    3050
    Completed
    150
    2824
    Not completed
    0
    226
         Protocol deviation
    -
    11
         Physician decision
    -
    7
         Pregnancy
    -
    6
         Adverse event, non-fatal
    -
    5
         Consent withdrawn by subject
    -
    120
         Lost to follow-up
    -
    77
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: Enrollment in Cohorts 1 and 2 was voluntary; not all eligible participants enrolled in these cohorts.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Low-dose V503
    Reporting group description
    V503 (9-Valent Human Papillomavirus [HPV] Vaccine) low-dose 0.5 mL injection in a 3-dose regimen in the Base Study.

    Reporting group title
    Mid-dose V503
    Reporting group description
    V503 mid-dose 0.5 mL injection in a 3-dose regimen in the Base Study. A subset of participants will receive a fourth V503 mid-dose vaccination in the extension study (Cohort 1).

    Reporting group title
    High-dose V503
    Reporting group description
    V503 high-dose 0.5 mL injection in a 3-dose regimen in the Base Study

    Reporting group title
    Gardasil
    Reporting group description
    Gardasil (4-Valent HPV Vaccine) 0.5 mL injection in a 3-dose regimen in the Base Study. Participants will be offered the V503 mid-dose 3-dose regimen in the extension study (Cohort 2).

    Reporting group values
    Low-dose V503 Mid-dose V503 High-dose V503 Gardasil Total
    Number of subjects
    315 7106 310 7109 14840
    Age Categorical
    Units: Subjects
        Adolescents (12-17 years)
    3 170 3 167 343
        Adults (18-64 years)
    312 6936 307 6942 14497
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    21.7 ± 2.4 21.9 ± 2.5 21.9 ± 2.4 21.8 ± 2.5 -
    Gender Categorical
    Units: Subjects
        Female
    315 7106 310 7109 14840
        Male
    0 0 0 0 0

    End points

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    End points reporting groups
    Reporting group title
    Low-dose V503
    Reporting group description
    V503 (9-Valent Human Papillomavirus [HPV] Vaccine) low-dose 0.5 mL injection in a 3-dose regimen in the Base Study.

    Reporting group title
    Mid-dose V503
    Reporting group description
    V503 mid-dose 0.5 mL injection in a 3-dose regimen in the Base Study. A subset of participants will receive a fourth V503 mid-dose vaccination in the extension study (Cohort 1).

    Reporting group title
    High-dose V503
    Reporting group description
    V503 high-dose 0.5 mL injection in a 3-dose regimen in the Base Study

    Reporting group title
    Gardasil
    Reporting group description
    Gardasil (4-Valent HPV Vaccine) 0.5 mL injection in a 3-dose regimen in the Base Study. Participants will be offered the V503 mid-dose 3-dose regimen in the extension study (Cohort 2).
    Reporting group title
    Mid-dose V503 (Cohort 1)
    Reporting group description
    V503 (9-Valent HPV Vaccine) mid-dose 0.5 mL fourth dose administration on Base Study participants who were randomized to receive a 3-dose regimen of V503 (9-Valent HPV) mid-dose 0.5 mL (Cohort 1).

    Reporting group title
    Mid-dose V503 (Cohort 2)
    Reporting group description
    V503 (9-Valent HPV Vaccine) mid-dose 0.5 mL 3-dose regimen administration on Base Study participants who were randomized to receive a 3-dose regimen of Gardasil (4-Valent HPV Vaccine) (Cohort 2).

    Primary: Base Study: Combined Incidence of HPV Type 31/33/45/52/58-related High-Grade Disease (Test of Hypothesis)

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    End point title
    Base Study: Combined Incidence of HPV Type 31/33/45/52/58-related High-Grade Disease (Test of Hypothesis) [1]
    End point description
    HPV Type 31/33/45/52/58-related high-grade Cervical Intraepithelial Neoplasia (CIN 2/3), Adenocarcinoma in Situ (AIS), Invasive Cervical Carcinoma, high-grade Vulvar Intraepithelial Neoplasia (VIN 2/3), high-grade Vaginal Intraepithelial Neoplasia (VaIN 2/3), vulvar cancer, or vaginal cancer were determined by clinical/pathologic criteria and positive Polymerase Chain Reaction (PCR) assay for virus subtype. This outcome measure reports data based on the protocol-specified plan of conducting hypothesis testing when at least 30 cases had accumulated. Disease incidence was defined as the number of primary efficacy cases per 10,000 person-years of follow-up in a treatment arm. The Per-protocol Efficacy population included all participants who received all 3 vaccinations of mid-dose V503 or Gardasil within acceptable day ranges, were seronegative at Day 1 and PCR negative at Day 1 through Day 7 to the relevant HPV types, and had at least 1 follow-up visit following Month 7.
    End point type
    Primary
    End point timeframe
    From Month 7 until >=30 cases accumulate, up to Month 54 in the base study
    Notes
    [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint applied only to the Mid-dose V503 and Gardasil groups.
    End point values
    Mid-dose V503 Gardasil
    Number of subjects analysed
    6016
    6017
    Units: Cases per 10,000 person-years follow-up
        number (not applicable)
    0.5
    15.8
    Statistical analysis title
    V503 Vaccine Efficacy
    Statistical analysis description
    Vaccine efficacy = 100 * [1 - (incidence rate with V503 / incidence rate with Gardasil)]
    Comparison groups
    Mid-dose V503 v Gardasil
    Number of subjects included in analysis
    12033
    Analysis specification
    Pre-specified
    Analysis type
    other [2]
    P-value
    < 0.0001
    Method
    Chan and Bohidar Exact Binomial
    Parameter type
    Vaccine Efficacy
    Point estimate
    96.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    80.9
         upper limit
    99.8
    Notes
    [2] - The pre-specified success criterion was a lower bound of the 95% confidence interval of observed efficacy of >25%

    Primary: Base Study: Combined Incidence of HPV Type 31/33/45/52/58-related High-Grade Disease (End-of-study Update)

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    End point title
    Base Study: Combined Incidence of HPV Type 31/33/45/52/58-related High-Grade Disease (End-of-study Update) [3]
    End point description
    HPV Type 31/33/45/52/58-related high-grade Cervical Intraepithelial Neoplasia (CIN 2/3), Adenocarcinoma in Situ (AIS), Invasive Cervical Carcinoma, high-grade Vulvar Intraepithelial Neoplasia (VIN 2/3), high-grade Vaginal Intraepithelial Neoplasia (VaIN 2/3), vulvar cancer, or vaginal cancer were determined by clinical/pathologic criteria and positive Polymerase Chain Reaction (PCR) assay for virus subtype. This outcome measure reports cumulative study data through 10 March 2014. Disease incidence was defined as the number of primary efficacy cases per 10,000 person-years of follow-up in a treatment arm. The Per-protocol Efficacy population included all participants who received all 3 vaccinations of mid-dose V503 or Gardasil within acceptable day ranges, were seronegative at Day 1 and PCR negative at Day 1 through Day 7 to the relevant HPV types, and had at least 1 follow-up visit following Month 7.
    End point type
    Primary
    End point timeframe
    From Month 7 up to Month 54 in the Base Study
    Notes
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint applied only to the mid-dose V503 and Gardasil groups.
    End point values
    Mid-dose V503 Gardasil
    Number of subjects analysed
    6016
    6017
    Units: Cases per 10,000 person-years follow-up
        number (not applicable)
    0.5
    19
    Statistical analysis title
    V503 Vaccine Efficacy (End-of-Study Update)
    Statistical analysis description
    Vaccine efficacy = 100 * [1 - (incidence rate with V503 / incidence rate with Gardasil)]
    Comparison groups
    Mid-dose V503 v Gardasil
    Number of subjects included in analysis
    12033
    Analysis specification
    Pre-specified
    Analysis type
    other [4]
    Method
    Parameter type
    Vaccine Efficacy
    Point estimate
    97.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    85
         upper limit
    99.9
    Notes
    [4] - The pre-specified success criterion was a lower bound of the 95% confidence interval of observed efficacy of >25%

    Primary: Base Study: Geometric Mean Titers (GMTs) to HPV Types 6/11/16/18/31/33/45/52/58

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    End point title
    Base Study: Geometric Mean Titers (GMTs) to HPV Types 6/11/16/18/31/33/45/52/58 [5]
    End point description
    Serum antibodies to HPV types 6/11/16/18/31/33/45/52/58 were measured with a Competitive Luminex Immunoassay. Titers are reported in milli Merck Units/mL. Statistical analysis was performed only for HPV types contained in both vaccines. The Per-protocol Immunogenicity population included all participants who were not protocol violators, received all 3vaccinations of mid-dose V503 or Gardasil within acceptable ranges, were seronegative at Day 1 and PCR negative from Day 1 to Month 7 for the relevant HPV types, and had a Month 7 serum sample collected within an acceptable range. A value of 9999 means less than the limit of quantification. Statistical analysis was performed only for HPV types contained in both vaccines.
    End point type
    Primary
    End point timeframe
    4 weeks postdose 3 in the Base Study
    Notes
    [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint applied only to the mid-dose V503 and Gardasil groups.
    End point values
    Mid-dose V503 Gardasil
    Number of subjects analysed
    6792
    6795
    Units: milli Merck U/mL
    geometric mean (confidence interval 95%)
        Anti-HPV Type 6 (n=3993, 3975)
    893.1 (871.7 to 915.1)
    875.2 (854.2 to 896.8)
        Anti-HPV Type 11 (n=3995, 3982)
    666.3 (649.6 to 683.4)
    830 (809.2 to 851.4)
        Anti-HPV Type 16 (n=4032, 4062)
    3131.1 (3057.1 to 3206.9)
    3156.6 (3082.3 to 3232.7)
        Anti-HPV Type 18 (n=4539, 4541)
    804.6 (782.7 to 827.1)
    678.7 (660.2 to 697.7)
        Anti-HPV Type 31 (n=4466, 4377)
    658.4 (636.7 to 680.9)
    9.7 (9.4 to 10.1)
        Anti-HPV Type 33 (n=4702, 4691)
    415.9 (405.6 to 426.4)
    9999 (9999 to 9999)
        Anti-HPV Type 45 (n=4792, 4750)
    252.8 (246.2 to 259.6)
    9999 (9999 to 9999)
        Anti-HPV Type 52 (n=4455, 4335)
    379.7 (371.6 to 388)
    9999 (9999 to 9999)
        Anti-HPV Type 58 (n=4486, 4446)
    482.5 (469.9 to 495.3)
    9999 (9999 to 9999)
    Statistical analysis title
    Non-inferiority anti-HPV Type 6
    Statistical analysis description
    Non-inferiority required that the lower bound of the two-sided confidence interval (CI) of the GMT ratio was >0.67
    Comparison groups
    Mid-dose V503 v Gardasil
    Number of subjects included in analysis
    13587
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    < 0.001
    Method
    ANOVA
    Parameter type
    GMT ratio = GMT (V503) / GMT (Gardasil)
    Point estimate
    1.02
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.99
         upper limit
    1.06
    Statistical analysis title
    Non-inferiority anti-HPV Type 16
    Statistical analysis description
    Non-inferiority required that the lower bound of the two-sided CI of the GMT ratio was >0.67
    Comparison groups
    Mid-dose V503 v Gardasil
    Number of subjects included in analysis
    13587
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    < 0.001
    Method
    ANOVA
    Parameter type
    GMT ratio = GMT (V503) / GMT (Gardasil)
    Point estimate
    0.99
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.96
         upper limit
    1.03
    Statistical analysis title
    Non-inferiority anti-HPV Type 11
    Statistical analysis description
    Non-inferiority required that the lower bound of the two-sided confidence interval (CI) of the GMT ratio was >0.67
    Comparison groups
    Mid-dose V503 v Gardasil
    Number of subjects included in analysis
    13587
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    < 0.001
    Method
    ANOVA
    Parameter type
    GMT ratio = GMT (V503) / GMT (Gardasil)
    Point estimate
    0.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.77
         upper limit
    0.83
    Statistical analysis title
    Non-inferiority anti-HPV Type 18
    Statistical analysis description
    Non-inferiority required that the lower bound of the two-sided CI of the GMT ratio was >0.67
    Comparison groups
    Mid-dose V503 v Gardasil
    Number of subjects included in analysis
    13587
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    < 0.001
    Method
    ANOVA
    Parameter type
    GMT ratio = GMT (V503) / GMT (Gardasil)
    Point estimate
    1.19
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.14
         upper limit
    1.23

    Primary: Base Study: Percentage of Participants With One or More Adverse Event

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    End point title
    Base Study: Percentage of Participants With One or More Adverse Event [6]
    End point description
    An adverse event (AE) is defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the study vaccine, whether or not considered related to the use of the product. Any worsening of a preexisting condition which is temporally associated with the use of the study vaccine is also an AE. The analysis population included all participants who received >=1 vaccination and had safety follow-up.
    End point type
    Primary
    End point timeframe
    Up to Month 7 (low- and high-dose V503) or up to Month 54 (mid-dose V503 and Gardasil)
    Notes
    [6] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was planned for Percentage of Participants With One or More Adverse Event.
    End point values
    Low-dose V503 Mid-dose V503 High-dose V503 Gardasil
    Number of subjects analysed
    310
    7071
    305
    7078
    Units: Percentage of participants
        number (not applicable)
    92.6
    94.2
    92.8
    91.1
    No statistical analyses for this end point

    Primary: Base Study: Percentage of Participants With One or More Injection-site Adverse Event

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    End point title
    Base Study: Percentage of Participants With One or More Injection-site Adverse Event [7]
    End point description
    An AE is defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the study vaccine, whether or not considered related to the use of the product. Any worsening of a preexisting condition which is temporally associated with the use of the study vaccine is also an AE. AEs such as redness, swelling, and pain/tenderness/soreness at the injection site were recorded. The analysis population included all participants who received >=1 vaccination and had safety follow-up.
    End point type
    Primary
    End point timeframe
    Up to Day 5 after any vaccination in the Base Study
    Notes
    [7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was planned for Percentage of Participants With One or More Injection-site Adverse Event.
    End point values
    Low-dose V503 Mid-dose V503 High-dose V503 Gardasil
    Number of subjects analysed
    310
    7071
    305
    7078
    Units: Percentage of participants
        number (not applicable)
    87.7
    90.7
    90.5
    84.9
    No statistical analyses for this end point

    Primary: Base Study: Percentage of Participants With One or More Non-injection-site (Systemic) Adverse Event

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    End point title
    Base Study: Percentage of Participants With One or More Non-injection-site (Systemic) Adverse Event [8]
    End point description
    An AE is defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the study vaccine, whether or not considered related to the use of the product. Any worsening of a preexisting condition which is temporally associated with the use of the study vaccine is also an AE. Systemic AEs were those not categorized as injection-site AEs. The analysis population included all participants who received >=1 vaccination and had safety follow-up.
    End point type
    Primary
    End point timeframe
    Up to Day 15 after any vaccination in the Base Study
    Notes
    [8] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was planned for Percentage of Participants With One or More Non-injection-site (Systemic) Adverse Event.
    End point values
    Low-dose V503 Mid-dose V503 High-dose V503 Gardasil
    Number of subjects analysed
    310
    7071
    305
    7078
    Units: Percentage of participants
        number (not applicable)
    53.5
    55.8
    51.1
    54.9
    No statistical analyses for this end point

    Primary: Base Study: Percentage of Participants With One or More Vaccine-related Adverse Event

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    End point title
    Base Study: Percentage of Participants With One or More Vaccine-related Adverse Event [9]
    End point description
    An AE is defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the study vaccine, whether or not considered related to the use of the product. Any worsening of a preexisting condition which is temporally associated with the use of the study vaccine is also an adverse event. An AE that is judged by the investigator to be “definitely related,” “probably related,” or “possibly related” to the study drug is defined as a vaccine-related AE. The analysis population included all participants who received >=1 vaccination and had safety follow-up.
    End point type
    Primary
    End point timeframe
    Up to Month 7 (low- and high-dose V503) or up to Month 54 (mid-dose V503 and Gardasil)
    Notes
    [9] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was planned for Percentage of Participants With One or More Vaccine-related Adverse Event.
    End point values
    Low-dose V503 Mid-dose V503 High-dose V503 Gardasil
    Number of subjects analysed
    310
    7071
    305
    7078
    Units: Percentage of participants
        number (not applicable)
    90
    92.2
    92.8
    87.6
    No statistical analyses for this end point

    Primary: Base Study: Percentage of Participants With Study Medication Withdrawn Due to an Adverse Event

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    End point title
    Base Study: Percentage of Participants With Study Medication Withdrawn Due to an Adverse Event [10]
    End point description
    An AE is defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the study vaccine, whether or not considered related to the use of the product. Any worsening of a preexisting condition which is temporally associated with the use of the study vaccine is also an AE. The analysis population included all participants who received >=1 vaccination and had safety follow-up.
    End point type
    Primary
    End point timeframe
    Up to Month 6
    Notes
    [10] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was planned for Percentage of Participants With Study Medication Withdrawn Due to an Adverse Event.
    End point values
    Low-dose V503 Mid-dose V503 High-dose V503 Gardasil
    Number of subjects analysed
    310
    7071
    305
    7078
    Units: Percentage of participants
        number (not applicable)
    0.6
    0.1
    0
    0.1
    No statistical analyses for this end point

    Primary: Extension Study (Immune Memory Substudy): Geometric Mean Titers to HPV Types 6/11/16/18/31/33/45/52/58 at Day 7 Postdose 4

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    End point title
    Extension Study (Immune Memory Substudy): Geometric Mean Titers to HPV Types 6/11/16/18/31/33/45/52/58 at Day 7 Postdose 4 [11]
    End point description
    Serum antibodies to HPV types 6/11/16/18/31/33/45/52/58 were measured with a Competitive Luminex Immunoassay. Titers are reported in milli Merck Units/mL. The Per-Protocol Immunogenicity population (Cohort 1) included all participants who were not protocol violators, received all 3 vaccinations of mid-dose V503 in the Base Study and a fourth dose in the Extension Study within acceptable ranges, were seronegative at Day 1 and PCR negative from Day 1 to Month7 for the relevant HPV types, and had a Month 60 serum sample collected within an acceptable range.
    End point type
    Primary
    End point timeframe
    Month 60 + 1 week: Day 7 postdose 4 in the Extension Study (Cohort 1)
    Notes
    [11] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was planned for Geometric Mean Titers to HPV Types 6/11/16/18/31/33/45/52/58 at Day 7 Postdose 4.
    End point values
    Mid-dose V503 (Cohort 1)
    Number of subjects analysed
    150
    Units: milli Merck U/mL
    geometric mean (confidence interval 95%)
        Anti-HPV Type 6 (n=109)
    2180.5 (1826.2 to 2603.7)
        Anti-HPV Type 11 (n=109)
    2228.7 (1852.5 to 2681.3)
        Anti-HPV Type 16 (n=126)
    7986.3 (6795.7 to 9385.6)
        Anti-HPV Type 18 (n=138)
    2399 (2049.4 to 2808.1)
        Anti-HPV Type 31 (n=131)
    1462.2 (1263.9 to 1691.5)
        Anti-HPV Type 33 (n=137)
    1709 (1466.7 to 1991.2)
        Anti-HPV Type 45 (n=144)
    323 (277.2 to 376.5)
        Anti-HPV Type 52 (n=131)
    1078.1 (907.2 to 1281.2)
        Anti-HPV Type 58 (n=129)
    1801.8 (1530.5 to 2121.2)
    No statistical analyses for this end point

    Primary: Extension Study (Immune Memory Substudy): Geometric Mean Titers to HPV Types 6/11/16/18/31/33/45/52/58 at Day 28 Postdose 4

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    End point title
    Extension Study (Immune Memory Substudy): Geometric Mean Titers to HPV Types 6/11/16/18/31/33/45/52/58 at Day 28 Postdose 4 [12]
    End point description
    Serum antibodies to HPV types 6/11/16/18/31/33/45/52/58 were measured with a Competitive Luminex Immunoassay. Titers are reported in milli Merck Units/mL. The Per-Protocol Immunogenicity population (Cohort 1) included all participants who were not protocol violators, received all 3 vaccinations of mid-dose V503 in the Base Study and a fourth dose in the Extension Study within acceptable ranges, were seronegative at Day 1 and PCR negative from Day 1 to Month7 for the relevant HPV types, and had a Month 60 serum sample collected within an acceptable range.
    End point type
    Primary
    End point timeframe
    Month 61: 28 days postdose 4 in the Extension Study (Cohort 1)
    Notes
    [12] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was planned for Geometric Mean Titers to HPV Types 6/11/16/18/31/33/45/52/58 at Day 28 Postdose 4.
    End point values
    Mid-dose V503 (Cohort 1)
    Number of subjects analysed
    150
    Units: milli Merck U/mL
    geometric mean (confidence interval 95%)
        Anti-HPV Type 6 (n=109)
    2585 (2239.5 to 2983.8)
        Anti-HPV Type 11 (n=109)
    2548.7 (2191.4 to 2964.3)
        Anti-HPV Type 16 (n=123)
    10904.3 (9605.6 to 12378.7)
        Anti-HPV Type 18 (n=137)
    2907.9 (2531.1 to 3340.7)
        Anti-HPV Type 31 (n=130)
    1745.4 (1538.8 to 1979.8)
        Anti-HPV Type 33 (n=136)
    2094.9 (1848.7 to 2373.9)
        Anti-HPV Type 45 (n=143)
    440 (386.9 to 500.4)
        Anti-HPV Type 52 (n=129)
    1131.5 (991.6 to 1291.1)
        Anti-HPV Type 58 (n=127)
    2024.6 (1803.1 to 2273.2)
    No statistical analyses for this end point

    Secondary: Base Study: Combined Incidence of HPV Type 31/33/45/52/58-related Persistent Infection

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    End point title
    Base Study: Combined Incidence of HPV Type 31/33/45/52/58-related Persistent Infection [13]
    End point description
    Combined Incidence of HPV Type 31/33/45/52/58-related persistent infection as determined by clinical/pathologic criteria and positive Polymerase Chain Reaction (PCR) assay for virus subtype. Persistent infection was defined as infection detected in samples from >=2 consecutive visits 6 months (+/-1 month visit window) or longer apart. Incidence was defined as the number of cases of persistent infection per 10,000 person-years of follow-up in a treatment arm. The Per-protocol Efficacy population included all participants who received all 3 vaccinations of mid-dose V503 or Gardasil within acceptable day ranges, were seronegative at Day 1 and PCR negative at Day 1 through Day 7 to the relevant HPV types, and had at least 1 follow-up visit following Month 7.
    End point type
    Secondary
    End point timeframe
    Up to Month 54 in the Base Study
    Notes
    [13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint applied only to the mid-dose V503 and Gardasil groups.
    End point values
    Mid-dose V503 Gardasil
    Number of subjects analysed
    5941
    5955
    Units: Cases per 10,000 person-years follow-up
        number (not applicable)
    21.5
    538.8
    Statistical analysis title
    Vaccine Efficacy
    Statistical analysis description
    Vaccine efficacy = 100 * [1 - (incidence rate with V503 / incidence rate with Gardasil)]
    Comparison groups
    Mid-dose V503 v Gardasil
    Number of subjects included in analysis
    11896
    Analysis specification
    Pre-specified
    Analysis type
    other [14]
    Method
    Parameter type
    Vaccine Efficacy
    Point estimate
    96
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    94.6
         upper limit
    97.1
    Notes
    [14] - The pre-specified success criterion was a lower bound of the 95% confidence interval of observed efficacy of >25%

    Secondary: Base Study: Percentage of Participants Who Are Seropositive for HPV Types 6/11/16/18/31/33/45/52/58

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    End point title
    Base Study: Percentage of Participants Who Are Seropositive for HPV Types 6/11/16/18/31/33/45/52/58 [15]
    End point description
    Serum antibodies to HPV types were measured with a Competitive Luminex Immunoassay. The serostatus cutoffs (milli Merck U/mL) for HPV types were as follows: HPV Type 6: ≥30; HPV Type 11: ≥16; HPV Type 16: ≥20; HPV Type 18: ≥24; HPV Type 31: ≥10; HPV Types 33, 45, 52, and 58: ≥8. The Per-protocol Immunogenicity population included all participants who were not protocol violators, received all 3 vaccinations of mid-dose V503 or Gardasil within acceptable ranges, were seronegative at Day 1 and PCR negative from Day 1 - Month 7 for the relevant HPV types, and had a Month 7 serum sample collected within an acceptable range.
    End point type
    Secondary
    End point timeframe
    4 weeks postdose 3 in the Base Study
    Notes
    [15] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint applied only to the mid-dose V503 and Gardasil groups.
    End point values
    Mid-dose V503 Gardasil
    Number of subjects analysed
    6792
    6795
    Units: Percentage of participants
    number (confidence interval 95%)
        Anti-HPV Type 6 (n=3993, 3975)
    99.8 (99.6 to 99.9)
    99.8 (99.7 to 99.9)
        Anti-HPV Type 11 (n=3995, 3982)
    100 (99.9 to 100)
    99.9 (99.8 to 100)
        Anti-HPV Type 16 (n=4032, 4062)
    100 (99.9 to 100)
    100 (99.9 to 100)
        Anti-HPV Type 18 (n=4539, 4541)
    99.9 (99.7 to 99.9)
    99.7 (99.5 to 99.8)
        Anti-HPV Type 31 (n=4466, 4377)
    99.8 (99.6 to 99.9)
    50.1 (48.7 to 51.6)
        Anti-HPV Type 33 (n=4702, 4691)
    99.7 (99.5 to 99.9)
    12.7 (11.8 to 13.7)
        Anti-HPV Type 45 (n=4792, 4750)
    99.6 (99.4 to 99.8)
    9.2 (8.4 to 10)
        Anti-HPV Type 52 (n=4455, 4335)
    99.8 (99.6 to 99.9)
    2.6 (2.2 to 3.1)
        Anti-HPV Type 58 (n=4486, 4446)
    99.8 (99.6 to 99.9)
    20.4 (19.2 to 21.6)
    No statistical analyses for this end point

    Other pre-specified: Extension Study (Immune Memory Substudy): Geometric Mean Titers to HPV Types 6/11/16/18/31/33/45/52/58 at Predose 4

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    End point title
    Extension Study (Immune Memory Substudy): Geometric Mean Titers to HPV Types 6/11/16/18/31/33/45/52/58 at Predose 4
    End point description
    Serum antibodies to HPV types 6/11/16/18/31/33/45/52/58 were measured with a Competitive Luminex Immunoassay. Titers are reported in milli Merck Units/mL. The Per-Protocol Immunogenicity population (Cohort 1) included all participants who were not protocol violators, received all 3 vaccinations of mid-dose V503 in the Base Study and a fourth dose in the Extension Study within acceptable ranges, were seronegative at Day 1 and PCR negative from Day 1 to Month7 for the relevant HPV types, and had a Month 60 serum sample collected within an acceptable range.
    End point type
    Other pre-specified
    End point timeframe
    Month 60: predose 4 in the Extension Study (Cohort 1)
    End point values
    Mid-dose V503 (Cohort 1)
    Number of subjects analysed
    150
    Units: milli Merck U/mL
    geometric mean (confidence interval 95%)
        Anti-HPV Type 6 (n=101)
    143.1 (117.9 to 173.7)
        Anti-HPV Type 11 (n=112)
    82.9 (68.1 to 100.9)
        Anti-HPV Type 16 (n=128)
    324.4 (266.7 to 394.7)
        Anti-HPV Type 18 (n=142)
    62.5 (49.5 to 78.9)
        Anti-HPV Type 31 (n=135)
    69.2 (56.6 to 84.4)
        Anti-HPV Type 33 (n=141)
    44.7 (37 to 54.1)
        Anti-HPV Type 45 (n=148)
    20.8 (17 to 25.5)
        Anti-HPV Type 52 (n=134)
    33.7 (27.6 to 41.1)
        Anti-HPV Type 58 (n=132)
    50.9 (40.9 to 63.3)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Base Study: SAEs up to Month (M) 7 (low- and high-dose V503) or up to M54 (mid-dose V503 and Gardasil); non-serious AEs up to Day 15 after vaccination. Cohort 1: SAEs M60 to 61; non-serious AEs up to Day 15 after vaccination 4. Cohort 2: SAEs M60 to 67.
    Adverse event reporting additional description
    The analysis population included all participants who received >=1 vaccination and had safety follow-up. Non-serious AEs were not solicited in Extension Cohort 2; however, some non-serious AEs were voluntarily reported.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    17.0
    Reporting groups
    Reporting group title
    Base Study: Low-dose V503
    Reporting group description
    V503 (9-Valent HPV Vaccine) low-dose 0.5 mL injection in a 3-dose regimen in the Base Study.

    Reporting group title
    Base Study: Mid-dose V503
    Reporting group description
    V503 mid-dose 0.5 mL injection in a 3-dose regimen in the Base Study.

    Reporting group title
    Base Study: High-dose V503
    Reporting group description
    V503 high-dose 0.5 mL injection in a 3-dose regimen in the Base Study.

    Reporting group title
    Base Study: Gardasil
    Reporting group description
    Gardasil (4-Valent HPV Vaccine) 0.5 mL injection in a 3-dose regimen in the Base Study. Participants will be offered the V503 mid-dose 3-dose regimen in the extension study (Cohort 2).

    Reporting group title
    Extension Study: Mid-dose V503 (Cohort 1)
    Reporting group description
    V503 (9-Valent HPV Vaccine) mid-dose 0.5 mL fourth dose administration on Base Study participants who were randomized to receive a 3-dose regimen of V503 (9-Valent HPV) mid-dose 0.5 mL (Cohort 1).

    Reporting group title
    Extension Study: Mid-dose V503 (Cohort 2)
    Reporting group description
    V503 (9-Valent HPV Vaccine) mid-dose 0.5 mL 3-dose regimen administration on Base Study participants who were randomized to receive a 3-dose regimen of Gardasil (4-Valent HPV Vaccine) (Cohort 2).

    Serious adverse events
    Base Study: Low-dose V503 Base Study: Mid-dose V503 Base Study: High-dose V503 Base Study: Gardasil Extension Study: Mid-dose V503 (Cohort 1) Extension Study: Mid-dose V503 (Cohort 2)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 310 (1.29%)
    233 / 7071 (3.30%)
    5 / 305 (1.64%)
    184 / 7078 (2.60%)
    1 / 150 (0.67%)
    25 / 3049 (0.82%)
         number of deaths (all causes)
    0
    6
    0
    5
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    Vascular disorders
    Axillary vein thrombosis
         subjects affected / exposed
    0 / 310 (0.00%)
    0 / 7071 (0.00%)
    0 / 305 (0.00%)
    1 / 7078 (0.01%)
    0 / 150 (0.00%)
    0 / 3049 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    0 / 310 (0.00%)
    1 / 7071 (0.01%)
    0 / 305 (0.00%)
    0 / 7078 (0.00%)
    0 / 150 (0.00%)
    0 / 3049 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypovolaemic shock
         subjects affected / exposed
    0 / 310 (0.00%)
    2 / 7071 (0.03%)
    0 / 305 (0.00%)
    0 / 7078 (0.00%)
    0 / 150 (0.00%)
    0 / 3049 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    Abortion induced
         subjects affected / exposed
    1 / 310 (0.32%)
    73 / 7071 (1.03%)
    2 / 305 (0.66%)
    53 / 7078 (0.75%)
    0 / 150 (0.00%)
    3 / 3049 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 76
    0 / 2
    0 / 53
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Acute lymphocytic leukaemia
         subjects affected / exposed
    0 / 310 (0.00%)
    1 / 7071 (0.01%)
    0 / 305 (0.00%)
    0 / 7078 (0.00%)
    0 / 150 (0.00%)
    0 / 3049 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute promyelocytic leukaemia
         subjects affected / exposed
    0 / 310 (0.00%)
    1 / 7071 (0.01%)
    0 / 305 (0.00%)
    0 / 7078 (0.00%)
    0 / 150 (0.00%)
    0 / 3049 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Adenocarcinoma gastric
         subjects affected / exposed
    0 / 310 (0.00%)
    0 / 7071 (0.00%)
    0 / 305 (0.00%)
    1 / 7078 (0.01%)
    0 / 150 (0.00%)
    0 / 3049 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Adenocarcinoma of the cervix
         subjects affected / exposed
    0 / 310 (0.00%)
    1 / 7071 (0.01%)
    0 / 305 (0.00%)
    0 / 7078 (0.00%)
    0 / 150 (0.00%)
    1 / 3049 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Brain neoplasm
         subjects affected / exposed
    0 / 310 (0.00%)
    1 / 7071 (0.01%)
    0 / 305 (0.00%)
    0 / 7078 (0.00%)
    0 / 150 (0.00%)
    0 / 3049 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ependymoma
         subjects affected / exposed
    0 / 310 (0.00%)
    1 / 7071 (0.01%)
    0 / 305 (0.00%)
    0 / 7078 (0.00%)
    0 / 150 (0.00%)
    0 / 3049 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Leukaemic infiltration brain
         subjects affected / exposed
    0 / 310 (0.00%)
    1 / 7071 (0.01%)
    0 / 305 (0.00%)
    0 / 7078 (0.00%)
    0 / 150 (0.00%)
    0 / 3049 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Malignant melanoma
         subjects affected / exposed
    0 / 310 (0.00%)
    2 / 7071 (0.03%)
    0 / 305 (0.00%)
    0 / 7078 (0.00%)
    0 / 150 (0.00%)
    0 / 3049 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Malignant melanoma in situ
         subjects affected / exposed
    0 / 310 (0.00%)
    1 / 7071 (0.01%)
    0 / 305 (0.00%)
    0 / 7078 (0.00%)
    0 / 150 (0.00%)
    0 / 3049 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Malignant palate neoplasm
         subjects affected / exposed
    0 / 310 (0.00%)
    0 / 7071 (0.00%)
    0 / 305 (0.00%)
    1 / 7078 (0.01%)
    0 / 150 (0.00%)
    0 / 3049 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nasal cavity cancer
         subjects affected / exposed
    0 / 310 (0.00%)
    1 / 7071 (0.01%)
    0 / 305 (0.00%)
    0 / 7078 (0.00%)
    0 / 150 (0.00%)
    0 / 3049 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ovarian neoplasm
         subjects affected / exposed
    0 / 310 (0.00%)
    1 / 7071 (0.01%)
    0 / 305 (0.00%)
    0 / 7078 (0.00%)
    0 / 150 (0.00%)
    0 / 3049 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pituitary tumour benign
         subjects affected / exposed
    0 / 310 (0.00%)
    0 / 7071 (0.00%)
    0 / 305 (0.00%)
    1 / 7078 (0.01%)
    0 / 150 (0.00%)
    0 / 3049 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory papilloma
         subjects affected / exposed
    0 / 310 (0.00%)
    0 / 7071 (0.00%)
    0 / 305 (0.00%)
    1 / 7078 (0.01%)
    0 / 150 (0.00%)
    0 / 3049 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thyroid cancer
         subjects affected / exposed
    0 / 310 (0.00%)
    0 / 7071 (0.00%)
    0 / 305 (0.00%)
    1 / 7078 (0.01%)
    0 / 150 (0.00%)
    0 / 3049 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Breast cancer
         subjects affected / exposed
    0 / 310 (0.00%)
    0 / 7071 (0.00%)
    0 / 305 (0.00%)
    0 / 7078 (0.00%)
    0 / 150 (0.00%)
    1 / 3049 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Glioma
         subjects affected / exposed
    0 / 310 (0.00%)
    0 / 7071 (0.00%)
    0 / 305 (0.00%)
    0 / 7078 (0.00%)
    0 / 150 (0.00%)
    1 / 3049 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Allergy to vaccine
         subjects affected / exposed
    0 / 310 (0.00%)
    1 / 7071 (0.01%)
    0 / 305 (0.00%)
    0 / 7078 (0.00%)
    0 / 150 (0.00%)
    0 / 3049 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anaphylactic reaction
         subjects affected / exposed
    0 / 310 (0.00%)
    1 / 7071 (0.01%)
    0 / 305 (0.00%)
    0 / 7078 (0.00%)
    0 / 150 (0.00%)
    0 / 3049 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypersensitivity
         subjects affected / exposed
    0 / 310 (0.00%)
    1 / 7071 (0.01%)
    0 / 305 (0.00%)
    0 / 7078 (0.00%)
    0 / 150 (0.00%)
    0 / 3049 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sarcoidosis
         subjects affected / exposed
    0 / 310 (0.00%)
    1 / 7071 (0.01%)
    0 / 305 (0.00%)
    0 / 7078 (0.00%)
    0 / 150 (0.00%)
    0 / 3049 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Abortion spontaneous
         subjects affected / exposed
    1 / 310 (0.32%)
    36 / 7071 (0.51%)
    1 / 305 (0.33%)
    26 / 7078 (0.37%)
    0 / 150 (0.00%)
    8 / 3049 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 38
    0 / 1
    0 / 28
    0 / 0
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abortion spontaneous complete
         subjects affected / exposed
    0 / 310 (0.00%)
    0 / 7071 (0.00%)
    0 / 305 (0.00%)
    2 / 7078 (0.03%)
    0 / 150 (0.00%)
    0 / 3049 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abortion spontaneous incomplete
         subjects affected / exposed
    0 / 310 (0.00%)
    1 / 7071 (0.01%)
    0 / 305 (0.00%)
    0 / 7078 (0.00%)
    0 / 150 (0.00%)
    0 / 3049 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blighted ovum
         subjects affected / exposed
    0 / 310 (0.00%)
    1 / 7071 (0.01%)
    0 / 305 (0.00%)
    1 / 7078 (0.01%)
    0 / 150 (0.00%)
    0 / 3049 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cephalo-pelvic disproportion
         subjects affected / exposed
    0 / 310 (0.00%)
    4 / 7071 (0.06%)
    0 / 305 (0.00%)
    6 / 7078 (0.08%)
    0 / 150 (0.00%)
    0 / 3049 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
    0 / 0
    0 / 6
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cervix dystocia
         subjects affected / exposed
    0 / 310 (0.00%)
    1 / 7071 (0.01%)
    0 / 305 (0.00%)
    1 / 7078 (0.01%)
    0 / 150 (0.00%)
    0 / 3049 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ectopic pregnancy
         subjects affected / exposed
    0 / 310 (0.00%)
    0 / 7071 (0.00%)
    0 / 305 (0.00%)
    1 / 7078 (0.01%)
    0 / 150 (0.00%)
    0 / 3049 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    False labour
         subjects affected / exposed
    0 / 310 (0.00%)
    1 / 7071 (0.01%)
    0 / 305 (0.00%)
    0 / 7078 (0.00%)
    0 / 150 (0.00%)
    0 / 3049 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Foetal death
         subjects affected / exposed
    0 / 310 (0.00%)
    1 / 7071 (0.01%)
    1 / 305 (0.33%)
    0 / 7078 (0.00%)
    0 / 150 (0.00%)
    0 / 3049 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Foetal distress syndrome
         subjects affected / exposed
    1 / 310 (0.32%)
    4 / 7071 (0.06%)
    0 / 305 (0.00%)
    1 / 7078 (0.01%)
    0 / 150 (0.00%)
    0 / 3049 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Foetal malposition
         subjects affected / exposed
    0 / 310 (0.00%)
    0 / 7071 (0.00%)
    0 / 305 (0.00%)
    1 / 7078 (0.01%)
    0 / 150 (0.00%)
    0 / 3049 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Foetal malpresentation
         subjects affected / exposed
    0 / 310 (0.00%)
    0 / 7071 (0.00%)
    0 / 305 (0.00%)
    1 / 7078 (0.01%)
    0 / 150 (0.00%)
    0 / 3049 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gestational diabetes
         subjects affected / exposed
    0 / 310 (0.00%)
    0 / 7071 (0.00%)
    0 / 305 (0.00%)
    1 / 7078 (0.01%)
    0 / 150 (0.00%)
    1 / 3049 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Labour complication
         subjects affected / exposed
    0 / 310 (0.00%)
    1 / 7071 (0.01%)
    0 / 305 (0.00%)
    0 / 7078 (0.00%)
    0 / 150 (0.00%)
    0 / 3049 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oligohydramnios
         subjects affected / exposed
    0 / 310 (0.00%)
    0 / 7071 (0.00%)
    0 / 305 (0.00%)
    1 / 7078 (0.01%)
    0 / 150 (0.00%)
    0 / 3049 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pre-eclampsia
         subjects affected / exposed
    0 / 310 (0.00%)
    1 / 7071 (0.01%)
    1 / 305 (0.33%)
    1 / 7078 (0.01%)
    0 / 150 (0.00%)
    0 / 3049 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Premature labour
         subjects affected / exposed
    0 / 310 (0.00%)
    1 / 7071 (0.01%)
    0 / 305 (0.00%)
    1 / 7078 (0.01%)
    0 / 150 (0.00%)
    0 / 3049 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Premature rupture of membranes
         subjects affected / exposed
    0 / 310 (0.00%)
    4 / 7071 (0.06%)
    0 / 305 (0.00%)
    2 / 7078 (0.03%)
    0 / 150 (0.00%)
    0 / 3049 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Prolonged labour
         subjects affected / exposed
    0 / 310 (0.00%)
    2 / 7071 (0.03%)
    0 / 305 (0.00%)
    1 / 7078 (0.01%)
    0 / 150 (0.00%)
    0 / 3049 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Uterine contractions during pregnancy
         subjects affected / exposed
    0 / 310 (0.00%)
    1 / 7071 (0.01%)
    0 / 305 (0.00%)
    0 / 7078 (0.00%)
    0 / 150 (0.00%)
    0 / 3049 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Accidental death
         subjects affected / exposed
    0 / 310 (0.00%)
    0 / 7071 (0.00%)
    0 / 305 (0.00%)
    1 / 7078 (0.01%)
    0 / 150 (0.00%)
    0 / 3049 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 310 (0.00%)
    0 / 7071 (0.00%)
    0 / 305 (0.00%)
    1 / 7078 (0.01%)
    0 / 150 (0.00%)
    0 / 3049 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 310 (0.00%)
    1 / 7071 (0.01%)
    0 / 305 (0.00%)
    0 / 7078 (0.00%)
    0 / 150 (0.00%)
    0 / 3049 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sudden death
         subjects affected / exposed
    0 / 310 (0.00%)
    1 / 7071 (0.01%)
    0 / 305 (0.00%)
    0 / 7078 (0.00%)
    0 / 150 (0.00%)
    0 / 3049 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Anorexia and bulimia syndrome
         subjects affected / exposed
    0 / 310 (0.00%)
    1 / 7071 (0.01%)
    0 / 305 (0.00%)
    0 / 7078 (0.00%)
    0 / 150 (0.00%)
    0 / 3049 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anorexia nervosa
         subjects affected / exposed
    0 / 310 (0.00%)
    0 / 7071 (0.00%)
    0 / 305 (0.00%)
    1 / 7078 (0.01%)
    0 / 150 (0.00%)
    0 / 3049 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bipolar disorder
         subjects affected / exposed
    0 / 310 (0.00%)
    3 / 7071 (0.04%)
    0 / 305 (0.00%)
    1 / 7078 (0.01%)
    0 / 150 (0.00%)
    0 / 3049 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Completed suicide
         subjects affected / exposed
    0 / 310 (0.00%)
    1 / 7071 (0.01%)
    0 / 305 (0.00%)
    0 / 7078 (0.00%)
    0 / 150 (0.00%)
    0 / 3049 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    0 / 310 (0.00%)
    0 / 7071 (0.00%)
    0 / 305 (0.00%)
    1 / 7078 (0.01%)
    0 / 150 (0.00%)
    0 / 3049 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Major depression
         subjects affected / exposed
    0 / 310 (0.00%)
    1 / 7071 (0.01%)
    0 / 305 (0.00%)
    0 / 7078 (0.00%)
    0 / 150 (0.00%)
    0 / 3049 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Bartholinitis
         subjects affected / exposed
    0 / 310 (0.00%)
    1 / 7071 (0.01%)
    0 / 305 (0.00%)
    0 / 7078 (0.00%)
    0 / 150 (0.00%)
    0 / 3049 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cervical dysplasia
         subjects affected / exposed
    0 / 310 (0.00%)
    5 / 7071 (0.07%)
    0 / 305 (0.00%)
    3 / 7078 (0.04%)
    0 / 150 (0.00%)
    0 / 3049 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 5
    0 / 0
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cervix haemorrhage uterine
         subjects affected / exposed
    0 / 310 (0.00%)
    1 / 7071 (0.01%)
    0 / 305 (0.00%)
    0 / 7078 (0.00%)
    0 / 150 (0.00%)
    0 / 3049 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dysmenorrhoea
         subjects affected / exposed
    0 / 310 (0.00%)
    0 / 7071 (0.00%)
    0 / 305 (0.00%)
    1 / 7078 (0.01%)
    0 / 150 (0.00%)
    0 / 3049 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endometriosis
         subjects affected / exposed
    0 / 310 (0.00%)
    2 / 7071 (0.03%)
    0 / 305 (0.00%)
    1 / 7078 (0.01%)
    0 / 150 (0.00%)
    0 / 3049 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fallopian tube cyst
         subjects affected / exposed
    0 / 310 (0.00%)
    0 / 7071 (0.00%)
    0 / 305 (0.00%)
    1 / 7078 (0.01%)
    0 / 150 (0.00%)
    0 / 3049 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ovarian cyst
         subjects affected / exposed
    0 / 310 (0.00%)
    1 / 7071 (0.01%)
    0 / 305 (0.00%)
    2 / 7078 (0.03%)
    0 / 150 (0.00%)
    0 / 3049 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pelvic pain
         subjects affected / exposed
    0 / 310 (0.00%)
    1 / 7071 (0.01%)
    0 / 305 (0.00%)
    0 / 7078 (0.00%)
    0 / 150 (0.00%)
    0 / 3049 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Bladder injury
         subjects affected / exposed
    0 / 310 (0.00%)
    1 / 7071 (0.01%)
    0 / 305 (0.00%)
    0 / 7078 (0.00%)
    0 / 150 (0.00%)
    0 / 3049 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Burns second degree
         subjects affected / exposed
    0 / 310 (0.00%)
    1 / 7071 (0.01%)
    0 / 305 (0.00%)
    0 / 7078 (0.00%)
    0 / 150 (0.00%)
    0 / 3049 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Craniocerebral injury
         subjects affected / exposed
    0 / 310 (0.00%)
    1 / 7071 (0.01%)
    0 / 305 (0.00%)
    0 / 7078 (0.00%)
    0 / 150 (0.00%)
    0 / 3049 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    0 / 310 (0.00%)
    1 / 7071 (0.01%)
    0 / 305 (0.00%)
    0 / 7078 (0.00%)
    0 / 150 (0.00%)
    1 / 3049 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Foreign body in eye
         subjects affected / exposed
    0 / 310 (0.00%)
    0 / 7071 (0.00%)
    0 / 305 (0.00%)
    1 / 7078 (0.01%)
    0 / 150 (0.00%)
    0 / 3049 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fracture displacement
         subjects affected / exposed
    0 / 310 (0.00%)
    0 / 7071 (0.00%)
    0 / 305 (0.00%)
    1 / 7078 (0.01%)
    0 / 150 (0.00%)
    0 / 3049 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hand fracture
         subjects affected / exposed
    0 / 310 (0.00%)
    0 / 7071 (0.00%)
    0 / 305 (0.00%)
    1 / 7078 (0.01%)
    0 / 150 (0.00%)
    0 / 3049 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Head injury
         subjects affected / exposed
    0 / 310 (0.00%)
    0 / 7071 (0.00%)
    0 / 305 (0.00%)
    1 / 7078 (0.01%)
    0 / 150 (0.00%)
    0 / 3049 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    0 / 310 (0.00%)
    1 / 7071 (0.01%)
    0 / 305 (0.00%)
    0 / 7078 (0.00%)
    0 / 150 (0.00%)
    0 / 3049 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Joint dislocation
         subjects affected / exposed
    0 / 310 (0.00%)
    0 / 7071 (0.00%)
    0 / 305 (0.00%)
    2 / 7078 (0.03%)
    0 / 150 (0.00%)
    0 / 3049 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ligament rupture
         subjects affected / exposed
    0 / 310 (0.00%)
    1 / 7071 (0.01%)
    0 / 305 (0.00%)
    0 / 7078 (0.00%)
    0 / 150 (0.00%)
    0 / 3049 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lower limb fracture
         subjects affected / exposed
    0 / 310 (0.00%)
    1 / 7071 (0.01%)
    0 / 305 (0.00%)
    0 / 7078 (0.00%)
    0 / 150 (0.00%)
    0 / 3049 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Multiple injuries
         subjects affected / exposed
    0 / 310 (0.00%)
    2 / 7071 (0.03%)
    0 / 305 (0.00%)
    0 / 7078 (0.00%)
    0 / 150 (0.00%)
    0 / 3049 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neck injury
         subjects affected / exposed
    0 / 310 (0.00%)
    0 / 7071 (0.00%)
    0 / 305 (0.00%)
    1 / 7078 (0.01%)
    0 / 150 (0.00%)
    0 / 3049 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Poisoning
         subjects affected / exposed
    0 / 310 (0.00%)
    0 / 7071 (0.00%)
    0 / 305 (0.00%)
    1 / 7078 (0.01%)
    0 / 150 (0.00%)
    0 / 3049 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Post procedural haemorrhage
         subjects affected / exposed
    0 / 310 (0.00%)
    0 / 7071 (0.00%)
    0 / 305 (0.00%)
    1 / 7078 (0.01%)
    0 / 150 (0.00%)
    0 / 3049 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pubis fracture
         subjects affected / exposed
    0 / 310 (0.00%)
    1 / 7071 (0.01%)
    0 / 305 (0.00%)
    0 / 7078 (0.00%)
    0 / 150 (0.00%)
    0 / 3049 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Road traffic accident
         subjects affected / exposed
    0 / 310 (0.00%)
    1 / 7071 (0.01%)
    0 / 305 (0.00%)
    0 / 7078 (0.00%)
    0 / 150 (0.00%)
    0 / 3049 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    0 / 310 (0.00%)
    1 / 7071 (0.01%)
    0 / 305 (0.00%)
    0 / 7078 (0.00%)
    0 / 150 (0.00%)
    0 / 3049 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal cord injury
         subjects affected / exposed
    0 / 310 (0.00%)
    0 / 7071 (0.00%)
    0 / 305 (0.00%)
    1 / 7078 (0.01%)
    0 / 150 (0.00%)
    0 / 3049 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Spinal cord injury cervical
         subjects affected / exposed
    0 / 310 (0.00%)
    0 / 7071 (0.00%)
    0 / 305 (0.00%)
    1 / 7078 (0.01%)
    0 / 150 (0.00%)
    0 / 3049 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Ulna fracture
         subjects affected / exposed
    0 / 310 (0.00%)
    0 / 7071 (0.00%)
    0 / 305 (0.00%)
    0 / 7078 (0.00%)
    0 / 150 (0.00%)
    1 / 3049 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Aortic valve incompetence
         subjects affected / exposed
    0 / 310 (0.00%)
    1 / 7071 (0.01%)
    0 / 305 (0.00%)
    0 / 7078 (0.00%)
    0 / 150 (0.00%)
    0 / 3049 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Postural orthostatic tachycardia syndrome
         subjects affected / exposed
    0 / 310 (0.00%)
    1 / 7071 (0.01%)
    0 / 305 (0.00%)
    0 / 7078 (0.00%)
    0 / 150 (0.00%)
    0 / 3049 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    0 / 310 (0.00%)
    0 / 7071 (0.00%)
    0 / 305 (0.00%)
    0 / 7078 (0.00%)
    0 / 150 (0.00%)
    1 / 3049 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Cleft lip and palate
         subjects affected / exposed
    0 / 310 (0.00%)
    0 / 7071 (0.00%)
    0 / 305 (0.00%)
    1 / 7078 (0.01%)
    0 / 150 (0.00%)
    0 / 3049 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diverticulitis Meckel's
         subjects affected / exposed
    0 / 310 (0.00%)
    0 / 7071 (0.00%)
    0 / 305 (0.00%)
    1 / 7078 (0.01%)
    0 / 150 (0.00%)
    0 / 3049 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Asthmatic crisis
         subjects affected / exposed
    0 / 310 (0.00%)
    1 / 7071 (0.01%)
    0 / 305 (0.00%)
    0 / 7078 (0.00%)
    0 / 150 (0.00%)
    0 / 3049 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    0 / 310 (0.00%)
    0 / 7071 (0.00%)
    0 / 305 (0.00%)
    1 / 7078 (0.01%)
    0 / 150 (0.00%)
    0 / 3049 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nasal polyps
         subjects affected / exposed
    0 / 310 (0.00%)
    0 / 7071 (0.00%)
    0 / 305 (0.00%)
    1 / 7078 (0.01%)
    0 / 150 (0.00%)
    0 / 3049 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    0 / 310 (0.00%)
    1 / 7071 (0.01%)
    0 / 305 (0.00%)
    0 / 7078 (0.00%)
    0 / 150 (0.00%)
    0 / 3049 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    0 / 310 (0.00%)
    1 / 7071 (0.01%)
    0 / 305 (0.00%)
    0 / 7078 (0.00%)
    0 / 150 (0.00%)
    0 / 3049 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 310 (0.00%)
    1 / 7071 (0.01%)
    0 / 305 (0.00%)
    0 / 7078 (0.00%)
    0 / 150 (0.00%)
    0 / 3049 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vocal cord polyp
         subjects affected / exposed
    0 / 310 (0.00%)
    1 / 7071 (0.01%)
    0 / 305 (0.00%)
    0 / 7078 (0.00%)
    0 / 150 (0.00%)
    0 / 3049 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 310 (0.00%)
    1 / 7071 (0.01%)
    0 / 305 (0.00%)
    1 / 7078 (0.01%)
    0 / 150 (0.00%)
    0 / 3049 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Benign intracranial hypertension
         subjects affected / exposed
    0 / 310 (0.00%)
    0 / 7071 (0.00%)
    0 / 305 (0.00%)
    1 / 7078 (0.01%)
    0 / 150 (0.00%)
    0 / 3049 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebral haemorrhage
         subjects affected / exposed
    0 / 310 (0.00%)
    0 / 7071 (0.00%)
    0 / 305 (0.00%)
    1 / 7078 (0.01%)
    0 / 150 (0.00%)
    0 / 3049 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Diabetic coma
         subjects affected / exposed
    0 / 310 (0.00%)
    1 / 7071 (0.01%)
    0 / 305 (0.00%)
    0 / 7078 (0.00%)
    0 / 150 (0.00%)
    0 / 3049 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    0 / 310 (0.00%)
    1 / 7071 (0.01%)
    0 / 305 (0.00%)
    1 / 7078 (0.01%)
    0 / 150 (0.00%)
    0 / 3049 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Facial paresis
         subjects affected / exposed
    0 / 310 (0.00%)
    0 / 7071 (0.00%)
    0 / 305 (0.00%)
    1 / 7078 (0.01%)
    0 / 150 (0.00%)
    0 / 3049 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    0 / 310 (0.00%)
    0 / 7071 (0.00%)
    0 / 305 (0.00%)
    1 / 7078 (0.01%)
    0 / 150 (0.00%)
    0 / 3049 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hydrocephalus
         subjects affected / exposed
    0 / 310 (0.00%)
    0 / 7071 (0.00%)
    0 / 305 (0.00%)
    1 / 7078 (0.01%)
    0 / 150 (0.00%)
    0 / 3049 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypersomnia
         subjects affected / exposed
    0 / 310 (0.00%)
    1 / 7071 (0.01%)
    0 / 305 (0.00%)
    0 / 7078 (0.00%)
    0 / 150 (0.00%)
    0 / 3049 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypoaesthesia
         subjects affected / exposed
    0 / 310 (0.00%)
    0 / 7071 (0.00%)
    0 / 305 (0.00%)
    1 / 7078 (0.01%)
    0 / 150 (0.00%)
    0 / 3049 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intracranial venous sinus thrombosis
         subjects affected / exposed
    0 / 310 (0.00%)
    1 / 7071 (0.01%)
    0 / 305 (0.00%)
    0 / 7078 (0.00%)
    0 / 150 (0.00%)
    0 / 3049 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Migraine
         subjects affected / exposed
    0 / 310 (0.00%)
    1 / 7071 (0.01%)
    0 / 305 (0.00%)
    0 / 7078 (0.00%)
    0 / 150 (0.00%)
    0 / 3049 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Multiple sclerosis
         subjects affected / exposed
    0 / 310 (0.00%)
    2 / 7071 (0.03%)
    0 / 305 (0.00%)
    1 / 7078 (0.01%)
    0 / 150 (0.00%)
    1 / 3049 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neuritis
         subjects affected / exposed
    0 / 310 (0.00%)
    0 / 7071 (0.00%)
    0 / 305 (0.00%)
    1 / 7078 (0.01%)
    0 / 150 (0.00%)
    0 / 3049 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Orthostatic intolerance
         subjects affected / exposed
    0 / 310 (0.00%)
    0 / 7071 (0.00%)
    0 / 305 (0.00%)
    1 / 7078 (0.01%)
    0 / 150 (0.00%)
    0 / 3049 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Presyncope
         subjects affected / exposed
    0 / 310 (0.00%)
    1 / 7071 (0.01%)
    0 / 305 (0.00%)
    0 / 7078 (0.00%)
    0 / 150 (0.00%)
    0 / 3049 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sciatica
         subjects affected / exposed
    0 / 310 (0.00%)
    1 / 7071 (0.01%)
    0 / 305 (0.00%)
    0 / 7078 (0.00%)
    0 / 150 (0.00%)
    0 / 3049 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sensory disturbance
         subjects affected / exposed
    0 / 310 (0.00%)
    1 / 7071 (0.01%)
    0 / 305 (0.00%)
    0 / 7078 (0.00%)
    0 / 150 (0.00%)
    0 / 3049 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spondylitic myelopathy
         subjects affected / exposed
    0 / 310 (0.00%)
    0 / 7071 (0.00%)
    0 / 305 (0.00%)
    1 / 7078 (0.01%)
    0 / 150 (0.00%)
    0 / 3049 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 310 (0.00%)
    2 / 7071 (0.03%)
    0 / 305 (0.00%)
    0 / 7078 (0.00%)
    0 / 150 (0.00%)
    0 / 3049 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tension headache
         subjects affected / exposed
    0 / 310 (0.00%)
    1 / 7071 (0.01%)
    0 / 305 (0.00%)
    1 / 7078 (0.01%)
    0 / 150 (0.00%)
    0 / 3049 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Trigeminal nerve disorder
         subjects affected / exposed
    0 / 310 (0.00%)
    0 / 7071 (0.00%)
    0 / 305 (0.00%)
    0 / 7078 (0.00%)
    0 / 150 (0.00%)
    1 / 3049 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo positional
         subjects affected / exposed
    0 / 310 (0.00%)
    1 / 7071 (0.01%)
    0 / 305 (0.00%)
    0 / 7078 (0.00%)
    0 / 150 (0.00%)
    0 / 3049 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 310 (0.00%)
    0 / 7071 (0.00%)
    0 / 305 (0.00%)
    2 / 7078 (0.03%)
    0 / 150 (0.00%)
    0 / 3049 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain lower
         subjects affected / exposed
    0 / 310 (0.00%)
    0 / 7071 (0.00%)
    0 / 305 (0.00%)
    1 / 7078 (0.01%)
    0 / 150 (0.00%)
    0 / 3049 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anal fistula
         subjects affected / exposed
    0 / 310 (0.00%)
    1 / 7071 (0.01%)
    0 / 305 (0.00%)
    0 / 7078 (0.00%)
    0 / 150 (0.00%)
    0 / 3049 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Coeliac disease
         subjects affected / exposed
    0 / 310 (0.00%)
    1 / 7071 (0.01%)
    0 / 305 (0.00%)
    0 / 7078 (0.00%)
    0 / 150 (0.00%)
    0 / 3049 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colitis ulcerative
         subjects affected / exposed
    0 / 310 (0.00%)
    0 / 7071 (0.00%)
    0 / 305 (0.00%)
    1 / 7078 (0.01%)
    0 / 150 (0.00%)
    0 / 3049 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Crohn's disease
         subjects affected / exposed
    0 / 310 (0.00%)
    1 / 7071 (0.01%)
    0 / 305 (0.00%)
    0 / 7078 (0.00%)
    0 / 150 (0.00%)
    0 / 3049 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 310 (0.00%)
    1 / 7071 (0.01%)
    0 / 305 (0.00%)
    0 / 7078 (0.00%)
    0 / 150 (0.00%)
    0 / 3049 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Enterocolitis
         subjects affected / exposed
    0 / 310 (0.00%)
    0 / 7071 (0.00%)
    0 / 305 (0.00%)
    1 / 7078 (0.01%)
    0 / 150 (0.00%)
    0 / 3049 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    0 / 310 (0.00%)
    1 / 7071 (0.01%)
    0 / 305 (0.00%)
    1 / 7078 (0.01%)
    0 / 150 (0.00%)
    0 / 3049 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemorrhoids
         subjects affected / exposed
    0 / 310 (0.00%)
    1 / 7071 (0.01%)
    0 / 305 (0.00%)
    0 / 7078 (0.00%)
    0 / 150 (0.00%)
    0 / 3049 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    0 / 310 (0.00%)
    1 / 7071 (0.01%)
    0 / 305 (0.00%)
    1 / 7078 (0.01%)
    0 / 150 (0.00%)
    0 / 3049 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Irritable bowel syndrome
         subjects affected / exposed
    0 / 310 (0.00%)
    1 / 7071 (0.01%)
    0 / 305 (0.00%)
    0 / 7078 (0.00%)
    0 / 150 (0.00%)
    0 / 3049 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Omental infarction
         subjects affected / exposed
    0 / 310 (0.00%)
    0 / 7071 (0.00%)
    0 / 305 (0.00%)
    1 / 7078 (0.01%)
    0 / 150 (0.00%)
    0 / 3049 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    0 / 310 (0.00%)
    0 / 7071 (0.00%)
    0 / 305 (0.00%)
    1 / 7078 (0.01%)
    0 / 150 (0.00%)
    0 / 3049 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Calculus ureteric
         subjects affected / exposed
    0 / 310 (0.00%)
    1 / 7071 (0.01%)
    0 / 305 (0.00%)
    0 / 7078 (0.00%)
    0 / 150 (0.00%)
    0 / 3049 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Calculus urinary
         subjects affected / exposed
    0 / 310 (0.00%)
    1 / 7071 (0.01%)
    0 / 305 (0.00%)
    0 / 7078 (0.00%)
    0 / 150 (0.00%)
    0 / 3049 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cystitis haemorrhagic
         subjects affected / exposed
    0 / 310 (0.00%)
    0 / 7071 (0.00%)
    0 / 305 (0.00%)
    1 / 7078 (0.01%)
    0 / 150 (0.00%)
    0 / 3049 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    0 / 310 (0.00%)
    1 / 7071 (0.01%)
    0 / 305 (0.00%)
    0 / 7078 (0.00%)
    0 / 150 (0.00%)
    0 / 3049 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    0 / 310 (0.00%)
    2 / 7071 (0.03%)
    0 / 305 (0.00%)
    0 / 7078 (0.00%)
    0 / 150 (0.00%)
    0 / 3049 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal failure acute
         subjects affected / exposed
    0 / 310 (0.00%)
    0 / 7071 (0.00%)
    0 / 305 (0.00%)
    1 / 7078 (0.01%)
    0 / 150 (0.00%)
    0 / 3049 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal colic
         subjects affected / exposed
    0 / 310 (0.00%)
    0 / 7071 (0.00%)
    0 / 305 (0.00%)
    0 / 7078 (0.00%)
    0 / 150 (0.00%)
    1 / 3049 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholangitis
         subjects affected / exposed
    0 / 310 (0.00%)
    1 / 7071 (0.01%)
    0 / 305 (0.00%)
    0 / 7078 (0.00%)
    0 / 150 (0.00%)
    0 / 3049 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    0 / 310 (0.00%)
    1 / 7071 (0.01%)
    0 / 305 (0.00%)
    1 / 7078 (0.01%)
    0 / 150 (0.00%)
    0 / 3049 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    0 / 310 (0.00%)
    1 / 7071 (0.01%)
    0 / 305 (0.00%)
    2 / 7078 (0.03%)
    0 / 150 (0.00%)
    0 / 3049 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholestasis of pregnancy
         subjects affected / exposed
    0 / 310 (0.00%)
    0 / 7071 (0.00%)
    0 / 305 (0.00%)
    0 / 7078 (0.00%)
    0 / 150 (0.00%)
    1 / 3049 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Urticaria
         subjects affected / exposed
    0 / 310 (0.00%)
    0 / 7071 (0.00%)
    0 / 305 (0.00%)
    0 / 7078 (0.00%)
    0 / 150 (0.00%)
    1 / 3049 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Fibromyalgia
         subjects affected / exposed
    0 / 310 (0.00%)
    0 / 7071 (0.00%)
    0 / 305 (0.00%)
    1 / 7078 (0.01%)
    0 / 150 (0.00%)
    0 / 3049 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myalgia
         subjects affected / exposed
    0 / 310 (0.00%)
    1 / 7071 (0.01%)
    0 / 305 (0.00%)
    0 / 7078 (0.00%)
    0 / 150 (0.00%)
    0 / 3049 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    0 / 310 (0.00%)
    1 / 7071 (0.01%)
    0 / 305 (0.00%)
    0 / 7078 (0.00%)
    0 / 150 (0.00%)
    0 / 3049 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    0 / 310 (0.00%)
    1 / 7071 (0.01%)
    0 / 305 (0.00%)
    0 / 7078 (0.00%)
    0 / 150 (0.00%)
    0 / 3049 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Abscess jaw
         subjects affected / exposed
    0 / 310 (0.00%)
    1 / 7071 (0.01%)
    0 / 305 (0.00%)
    0 / 7078 (0.00%)
    0 / 150 (0.00%)
    0 / 3049 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    1 / 310 (0.32%)
    9 / 7071 (0.13%)
    0 / 305 (0.00%)
    16 / 7078 (0.23%)
    0 / 150 (0.00%)
    2 / 3049 (0.07%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 9
    0 / 0
    0 / 16
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    0 / 310 (0.00%)
    0 / 7071 (0.00%)
    0 / 305 (0.00%)
    2 / 7078 (0.03%)
    0 / 150 (0.00%)
    0 / 3049 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 310 (0.00%)
    0 / 7071 (0.00%)
    0 / 305 (0.00%)
    1 / 7078 (0.01%)
    0 / 150 (0.00%)
    0 / 3049 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis infective
         subjects affected / exposed
    0 / 310 (0.00%)
    1 / 7071 (0.01%)
    0 / 305 (0.00%)
    0 / 7078 (0.00%)
    0 / 150 (0.00%)
    0 / 3049 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chronic tonsillitis
         subjects affected / exposed
    0 / 310 (0.00%)
    1 / 7071 (0.01%)
    0 / 305 (0.00%)
    0 / 7078 (0.00%)
    0 / 150 (0.00%)
    0 / 3049 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Conjunctivitis
         subjects affected / exposed
    0 / 310 (0.00%)
    0 / 7071 (0.00%)
    0 / 305 (0.00%)
    1 / 7078 (0.01%)
    0 / 150 (0.00%)
    0 / 3049 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dengue fever
         subjects affected / exposed
    0 / 310 (0.00%)
    1 / 7071 (0.01%)
    0 / 305 (0.00%)
    0 / 7078 (0.00%)
    0 / 150 (0.00%)
    0 / 3049 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Enteritis infectious
         subjects affected / exposed
    0 / 310 (0.00%)
    2 / 7071 (0.03%)
    0 / 305 (0.00%)
    0 / 7078 (0.00%)
    0 / 150 (0.00%)
    0 / 3049 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 310 (0.00%)
    1 / 7071 (0.01%)
    0 / 305 (0.00%)
    2 / 7078 (0.03%)
    0 / 150 (0.00%)
    0 / 3049 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    0 / 310 (0.00%)
    1 / 7071 (0.01%)
    0 / 305 (0.00%)
    0 / 7078 (0.00%)
    0 / 150 (0.00%)
    0 / 3049 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemorrhagic fever
         subjects affected / exposed
    0 / 310 (0.00%)
    1 / 7071 (0.01%)
    0 / 305 (0.00%)
    0 / 7078 (0.00%)
    0 / 150 (0.00%)
    0 / 3049 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infectious mononucleosis
         subjects affected / exposed
    0 / 310 (0.00%)
    1 / 7071 (0.01%)
    0 / 305 (0.00%)
    0 / 7078 (0.00%)
    0 / 150 (0.00%)
    0 / 3049 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 310 (0.00%)
    1 / 7071 (0.01%)
    0 / 305 (0.00%)
    1 / 7078 (0.01%)
    0 / 150 (0.00%)
    0 / 3049 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pelvic inflammatory disease
         subjects affected / exposed
    0 / 310 (0.00%)
    0 / 7071 (0.00%)
    0 / 305 (0.00%)
    1 / 7078 (0.01%)
    0 / 150 (0.00%)
    0 / 3049 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pharyngitis
         subjects affected / exposed
    0 / 310 (0.00%)
    1 / 7071 (0.01%)
    0 / 305 (0.00%)
    0 / 7078 (0.00%)
    0 / 150 (0.00%)
    0 / 3049 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Post abortion infection
         subjects affected / exposed
    0 / 310 (0.00%)
    0 / 7071 (0.00%)
    0 / 305 (0.00%)
    1 / 7078 (0.01%)
    0 / 150 (0.00%)
    0 / 3049 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    0 / 310 (0.00%)
    2 / 7071 (0.03%)
    0 / 305 (0.00%)
    1 / 7078 (0.01%)
    0 / 150 (0.00%)
    0 / 3049 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis acute
         subjects affected / exposed
    0 / 310 (0.00%)
    1 / 7071 (0.01%)
    0 / 305 (0.00%)
    2 / 7078 (0.03%)
    0 / 150 (0.00%)
    0 / 3049 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    0 / 310 (0.00%)
    1 / 7071 (0.01%)
    0 / 305 (0.00%)
    0 / 7078 (0.00%)
    0 / 150 (0.00%)
    0 / 3049 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tonsillitis
         subjects affected / exposed
    0 / 310 (0.00%)
    1 / 7071 (0.01%)
    0 / 305 (0.00%)
    0 / 7078 (0.00%)
    0 / 150 (0.00%)
    0 / 3049 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tonsillitis streptococcal
         subjects affected / exposed
    0 / 310 (0.00%)
    1 / 7071 (0.01%)
    0 / 305 (0.00%)
    0 / 7078 (0.00%)
    0 / 150 (0.00%)
    0 / 3049 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 310 (0.00%)
    2 / 7071 (0.03%)
    1 / 305 (0.33%)
    2 / 7078 (0.03%)
    0 / 150 (0.00%)
    0 / 3049 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    0 / 310 (0.00%)
    1 / 7071 (0.01%)
    0 / 305 (0.00%)
    0 / 7078 (0.00%)
    0 / 150 (0.00%)
    0 / 3049 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Viral pharyngitis
         subjects affected / exposed
    0 / 310 (0.00%)
    0 / 7071 (0.00%)
    0 / 305 (0.00%)
    1 / 7078 (0.01%)
    0 / 150 (0.00%)
    0 / 3049 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Wound infection
         subjects affected / exposed
    0 / 310 (0.00%)
    1 / 7071 (0.01%)
    0 / 305 (0.00%)
    0 / 7078 (0.00%)
    0 / 150 (0.00%)
    0 / 3049 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 310 (0.00%)
    0 / 7071 (0.00%)
    0 / 305 (0.00%)
    0 / 7078 (0.00%)
    0 / 150 (0.00%)
    1 / 3049 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Postoperative wound infection
         subjects affected / exposed
    0 / 310 (0.00%)
    0 / 7071 (0.00%)
    0 / 305 (0.00%)
    0 / 7078 (0.00%)
    1 / 150 (0.67%)
    0 / 3049 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Base Study: Low-dose V503 Base Study: Mid-dose V503 Base Study: High-dose V503 Base Study: Gardasil Extension Study: Mid-dose V503 (Cohort 1) Extension Study: Mid-dose V503 (Cohort 2)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    278 / 310 (89.68%)
    6551 / 7071 (92.65%)
    280 / 305 (91.80%)
    6268 / 7078 (88.56%)
    130 / 150 (86.67%)
    89 / 3049 (2.92%)
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    17 / 310 (5.48%)
    346 / 7071 (4.89%)
    11 / 305 (3.61%)
    307 / 7078 (4.34%)
    0 / 150 (0.00%)
    2 / 3049 (0.07%)
         occurrences all number
    20
    405
    13
    368
    0
    2
    Headache
         subjects affected / exposed
    65 / 310 (20.97%)
    1879 / 7071 (26.57%)
    66 / 305 (21.64%)
    1756 / 7078 (24.81%)
    32 / 150 (21.33%)
    11 / 3049 (0.36%)
         occurrences all number
    100
    3071
    106
    2788
    41
    13
    General disorders and administration site conditions
    Injection site erythema
         subjects affected / exposed
    100 / 310 (32.26%)
    2411 / 7071 (34.10%)
    91 / 305 (29.84%)
    1810 / 7078 (25.57%)
    33 / 150 (22.00%)
    9 / 3049 (0.30%)
         occurrences all number
    157
    3597
    140
    2564
    34
    9
    Injection site pain
         subjects affected / exposed
    267 / 310 (86.13%)
    6360 / 7071 (89.94%)
    273 / 305 (89.51%)
    5911 / 7078 (83.51%)
    124 / 150 (82.67%)
    59 / 3049 (1.94%)
         occurrences all number
    684
    15383
    672
    13001
    128
    94
    Injection site pruritus
         subjects affected / exposed
    18 / 310 (5.81%)
    389 / 7071 (5.50%)
    14 / 305 (4.59%)
    282 / 7078 (3.98%)
    1 / 150 (0.67%)
    1 / 3049 (0.03%)
         occurrences all number
    21
    494
    16
    341
    1
    1
    Injection site swelling
         subjects affected / exposed
    100 / 310 (32.26%)
    2836 / 7071 (40.11%)
    103 / 305 (33.77%)
    2035 / 7078 (28.75%)
    49 / 150 (32.67%)
    12 / 3049 (0.39%)
         occurrences all number
    154
    4527
    168
    2988
    51
    12
    Pyrexia
         subjects affected / exposed
    30 / 310 (9.68%)
    469 / 7071 (6.63%)
    17 / 305 (5.57%)
    463 / 7078 (6.54%)
    6 / 150 (4.00%)
    7 / 3049 (0.23%)
         occurrences all number
    35
    563
    19
    550
    6
    7
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    22 / 310 (7.10%)
    513 / 7071 (7.25%)
    18 / 305 (5.90%)
    459 / 7078 (6.48%)
    2 / 150 (1.33%)
    4 / 3049 (0.13%)
         occurrences all number
    23
    617
    20
    551
    2
    4
    Infections and infestations
    Influenza
         subjects affected / exposed
    20 / 310 (6.45%)
    312 / 7071 (4.41%)
    12 / 305 (3.93%)
    296 / 7078 (4.18%)
    4 / 150 (2.67%)
    5 / 3049 (0.16%)
         occurrences all number
    22
    343
    12
    314
    5
    5
    Nasopharyngitis
         subjects affected / exposed
    10 / 310 (3.23%)
    376 / 7071 (5.32%)
    12 / 305 (3.93%)
    389 / 7078 (5.50%)
    1 / 150 (0.67%)
    0 / 3049 (0.00%)
         occurrences all number
    11
    412
    13
    420
    1
    0

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    24 Nov 2008
    Amendment 1: Revised the primary objective and hypothesis for measuring efficacy of the V503 vaccine against infection and disease caused by HPV Types 31, 33, 45, 52, and 58.
    18 Aug 2011
    Amendment 2: Updated the data analysis related to the secondary objective pertaining to reduction in combined incidence of HPV Types 31, 33, 45, 52, and 58-related persistent infection. Specifically, the statistical criterion for success relating to the lower bound of the 95% confidence interval was changed from 0% to 25%.
    04 May 2012
    Amendment 3: Added two study visits, Month 48 and Month 54, to help ensure that an adequate number of primary efficacy endpoints were accrued to perform the primary efficacy analysis before the study ended.
    14 Oct 2013
    Amendment 4: Added an extension to the V503-001 Base Study, with the goals to 1) assess whether immunogenicity of a fourth dose of V503 vaccine shows evidence of immune memory, and 2) to offer a 3-dose regimen of V503 vaccine to participants in the control arm of the study.

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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